Histotripsy, or pulsed ultrasound cavitation therapy, is a technology where short, intense bursts of acoustic energy induce controlled cavitation (microbubble or bubble cloud formation) within the focal volume. The vigorous expansion and collapse of these microbubbles mechanically homogenizes cells and tissue structures within the focal volume. This is a very different end result than the coagulative necrosis characteristic of thermal ablation. To operate within a non-thermal, Histotripsy realm; it is necessary to deliver acoustic energy in the form of high pressure amplitude acoustic pulses with low duty cycle.
Compared with conventional focused ultrasound technologies, Histotripsy has important advantages: 1) the destructive process at the focus is mechanical, not thermal; 2) bubble clouds appear bright on ultrasound imaging thereby confirming correct targeting and localization of treatment; 3) treated tissue appears darker (hypoechoic) on ultrasound imaging, so that the operator knows what has been treated; and 4) Histotripsy produces lesions in a controlled and precise manner. It is important to emphasize that unlike microwave, radiofrequency, or high-intensity focused ultrasound (HIFU), Histotripsy is not a thermal modality.
Early canine studies of Histotripsy homogenization of prostate tissue employed a therapy transducer that was positioned to deliver Histotripsy transabdominally. In these studies, the prostate was located only a short distance from the skin surface and there was a relatively wide path from the transducer through the skin to focus ultrasound energy. Consequently, the spherical Histotripsy therapy transducer employed in these studies had 14 cm aperture and 10 cm focal length (F-number=0.71). Histotripsy therapy transducers with high F-numbers have very low efficiency compared to transducers with low F-numbers. These inefficiencies are primarily due to nonlinear acoustic propagation leading to shockwave formation.
Specialized therapy transducer and drive electronics have been designed to focus Histotripsy therapy through the perineum to the prostate. One example of a therapy transducer 100 configured to deliver Histotripsy therapy to the prostate is shown in FIG. 1. The transducer 100 can comprise a plurality of ultrasound transducer elements 102 disposed within housing 104. The transducer can be connected to a waveform generator configured to deliver Histotripsy waveforms from the transducer to tissue. The prostate depth from this approach is significantly deeper than in the canine model above. Additionally, the skeletal anatomy of the pelvis and transrectal position of the ultrasound imaging probe significantly reduced the effective transducer aperture. A cut-out 106 in the lower perimeter of housing can be configured to accommodate an ultrasound imaging probe (not shown) which has an F-number=0.85 in the main diameter and F-number=0.98 at the cut out.
Based on bench-top experimentation and modeling, an initial set of therapy transducer excitation parameters (3 cycles/pulse, 750 Vpp, 500 Hz PRF (Pulse Repetition Frequency)) was selected for canine testing with this transducer. This excitation sequence produced a non-linear focal pressure waveform with a peak negative and peak positive pressure of approximately 25 MPa and 100 MPa in water. We define this sequence and its variants as a, standard, or non-optimized, sequence because the sequence parameters were not optimized for bubble cloud formation.
This standard excitation sequence and variants were used to treat approximately 30 canine subjects to establish feasibility, dosing (cumulative number of pulses), and treatment implementation guidelines. An additional 10 canine subjects were then treated in a confirmatory study. Although, these studies yielded outstanding efficacy results, the observation of apparent minor injury (subclinical fibrosis) to the prefocal abdominal rectus muscle in 2 of 10 subjects in the confirmatory trial led to the conclusion that the safety profile needed to be improved by developing Histotripsy pulse sequences that deliver energy more efficiently. It is likely that the need to improve the efficiency of Histotripsy will become more important as transducers are developed to go deeper into tissues through skeletal anatomical obstructions.